The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia

Ma, Hu; Mallampati, Saradhi; Lu, Yue; Sun, Baohua; Wang, Enze; Leng, Xiaohong; Gong, Yun; Shen, Haifa; Yin, C. Cameron; Jones, Dan; Amin, Hesham M.; You, Mingliang; Zweidler‐McKay, Patrick A.; Ma, Yupo; Kantarjian, Hagop M.; Arlinghaus, Ralph B.; Glassman, Armand B.; Sun, Xiaoping

doi:10.3324/haematol.2014.104695

Cited by 24 publications

(20 citation statements)

References 29 publications

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“…SOX4 is highly expressed in human acute lymphoblastic leukemia cells and SOX4/Tcf7l1 is a functional axis that promotes the progression of BCR-ABL+ acute lymphoblastic leukemia. 31 In our study, we found that the expression of SOX4 was upregulated in three CC cell lines, particularly in CaSki cells, and in cervical squamous carcinoma tissues, suggesting that SOX4 may be involved in the progression of CC.…”

Section: Discussionsupporting

confidence: 48%

SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2

Sun

Jiang

et al. 2015

Cell Death Dis

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SOX4, a member of the SOX (sex-determining region Y-related HMG box) transcription factor family, has been reported to be abnormally expressed in a wide variety of cancers, and to exert a pleiotropic function. However, its function in progression of cervical cancer (CC) remains unknown. In this study, we found that SOX4 was highly expressed in CC cells and tissues, and overexpression of SOX4 in CC CaSki cells enhanced tumor clone formation and cell proliferation, and accelerated cell cycle progress. Meanwhile, downregulation of SOX4 by shRNA in CaSki cells inhibited cell proliferation, and slowed cell cycle progress, indicating that SOX4 contributes to the development of CC. In addition, SOX4 overexpression by gene transfer reduced the sensitivity of CaSki cells in response to the chemotherapeutic drug cisplatin, and SOX4 downregulation by RNA interference increased the sensitivity of CaSki cells in response to cisplatin. Moreover, SOX4 overexpression upregulated multiple drug resistant gene ABCG2, and SOX4 downregulation inhibited ABCG2 expression. Taken together, these results suggested that SOX4 functions to modulate cancer proliferation by regulation of cell cycle, and inhibit cancer cell sensitivity to therapeutic drug via upregulation of ABCG2. Thus, SOX4 may be a target for CC chemotherapy.

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Section: Discussionsupporting

confidence: 48%

SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2

Sun

Jiang

et al. 2015

Cell Death Dis

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“…Dysregulated targets in this process are stem cell factor SOX4 and MYC [ 20 , 54 , 55 ]. SOX4 also promotes progression in BCR-ABL positive acute lymphoblastic leukemia [ 56 ]. Consequently, analysis of other pathways and miR-212 targets could reveal further mechanisms causing the observed miR-212 effect on IM-susceptibility, especially in cells that underwent long-term or high dose treatment with IM.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

et al. 2017

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BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3′-UTR. However, the functional impact on drug sensitivity remained unknown. Therefore, we performed transfection experiments using microRNA-mimics and –inhibitors and investigated their effect on imatinib-susceptibility in sensitive and resistant leukemic cell lines. Under imatinib-treatment, miR-212 inhibition led to enhanced cell viability (p = 0.01), reduced apoptosis (p = 0.01) and cytotoxicity (p = 0.03). These effects were limited to treatment-naïve cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 μM to 2 μM). Further analysis in treatment-naïve cells revealed that miR-212 inhibition resulted in ABCG2 upregulation and increased ABCG2-dependent efflux. Furthermore, we observed miR-212 promoter hypermethylation in 0.5 and 2 μM IM-resistant sublines, whereas ABCG2 methylation status was not altered. Taken together, the miR-212/ABCG2-axis influences imatinib-susceptibility contributing to development of imatinib-resistance. Our data reveal new insights into mechanisms initiating imatinib-resistance in leukemic cells.

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“…This is illustrated by recent literature showing that activation of the Wnt pathway via TCF7L1 knockdown slowed growth of breast cancer xenograft tumors 16 and reduced proliferation of acute lymphoblastic leukemia cells 17 . In addition, a number of genes which have been identified as direct targets of CTNNB1/TCF transcriptional complexes correlate with improved CRC patient survival and have been shown to reduce CRC cell and tumor growth, such as CDX2 18 and EPHB3 19 20 .…”

mentioning

confidence: 86%

TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3

Murphy

Chatterjee

Jain

et al. 2016

Sci Rep

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Dysregulation of the Wnt pathway leading to accumulation of β-catenin (CTNNB1) is a hallmark of colorectal cancer (CRC). Nuclear CTNNB1 acts as a transcriptional coactivator with TCF/LEF transcription factors, promoting expression of a broad set of target genes, some of which promote tumor growth. However, it remains poorly understood how CTNNB1 interacts with different transcription factors in different contexts to promote different outcomes. While some CTNNB1 target genes are oncogenic, others regulate differentiation. Here, we found that TCF7L1, a Wnt pathway repressor, buffers CTNNB1/TCF target gene expression to promote CRC growth. Loss of TCF7L1 impaired growth and colony formation of HCT116 CRC cells and reduced tumor growth in a mouse xenograft model. We identified a group of CTNNB1/TCF target genes that are activated in the absence of TCF7L1, including EPHB3, a marker of Paneth cell differentiation that has also been implicated as a tumor suppressor in CRC. Knockdown of EPHB3 partially restores growth and normal cell cycle progression of TCF7L1-Null cells. These findings suggest that while CTNNB1 accumulation is critical for CRC progression, activation of specific Wnt target genes in certain contexts may in fact inhibit tumor growth.

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The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia

Cited by 24 publications

References 29 publications

SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2

SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3

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